Our understanding and treatment of serious mental illness, including schizophrenia, has lagged that for other major medical illnesses for at least two important reasons, including 1) the unparalleled complexity of the human brain and our only nascent understanding of psychiatric disease pathophysiology, and 2) the still limited translational tools available for testing and validating putative mechanisms in humans in vivo. In what many are hailing as a breakthrough in our neurobiological understanding of schizophrenia, Sekar and colleagues recently implicated an ?immune system protein,? complement component 4 (C4), in its etiology. Guided by a dramatic, albeit unexplained, genome-wide significant association in the major histocompatibility complex, they identified 1) complex structural variation in the C4 gene that was associated with parallel, dose- dependent increases in both schizophrenia risk and brain C4A RNA expression, 2) elevations in C4A RNA in post- mortem brain tissue from schizophrenia patients, and 3) using a mouse genetic model, a promising pathophysiological mechanism (i.e., aberrant synaptic pruning), whereby elevated C4A levels lead to disrupted synaptic integrity. To date, however, the relevance of this mechanism has yet to be established for the living human brain. Our group has developed a novel radiotracer, 11C-UCB-J, which now enables the imaging of synaptic density in the living human brain with positron-emission tomography (PET). The current exploratory/developmental (R21) application will apply this breakthrough methodology to explore whether genetic variation in C4 is associated with altered synaptic density in humans. If confirmed, the current study would provide compelling support for the aberrant synaptic pruning hypothesis of C4-mediated risk for schizophrenia, for the first time in the living human brain. As such, it would validate and build-upon a crucial breakthrough in our mechanistic understanding of schizophrenia and its causes.